This invention relates to ethylamine derivatives that function as a motilin receptor antagonist and that are useful as medicines.
Motilin, which is one of the gastrointestinal hormones, is a straight-chained peptide consisting of 22 amino acids and is well known to be responsible for regulating the motility of the gastrointestinal tract in animals including human. It has been reported that exogenously administered motilin causes contractions in humans and dogs that are similar to interdigestive migrating contractions, thus promoting gastric emptying (Itoh et al., Scand. J. Gastroenterol., 11, 93-110 (1976); Peeters et al., Gastroenterology 102, 97-101 (1992)). Hence, erythromycin derivatives which are an agonist of motilin are under development as an gastrointestinal tract motor activity enhancer (Satoh et al., J. Pharmacol. Exp. Therap., 271, 574-579 (1994); Lartey et al., J. Med. Chem., 38, 1793-1798 (1995); Drug of the Future, 19, 910-912 (1994)).
Peptide and polypeptide derivatives have been reported as antagonists of motilin receptors (Depoortere et al., Eur. J. Pharmacol., 286, 241-247 (1995); Poitras et al., Biochem. Biophys. Res. Commun., 205, 449-454 (1994); Takanashi et al., J. Pharmacol. Exp. Ther., 273, 624-628 (1995)). These derivatives are used as a pharmacological tool in the study of the action of motilin on the motility of the gastrointestinal tract and in the research and development of medicines in the field of the art contemplated by the invention.
Motilin receptors had been known to occur principally in the duodenum but recently it has been shown that they also occur in the large intestine, or the lower part of the gastrointestinal tract (William et al., Am. J. Physiol., 262, G50-G55 (1992)), and this indicates the possibility that motilin is involved not only in the motility of the upper part of the gastrointestinal tract but also in the motility of its lower part.
Reports have also been made of the cases of hypermotilinemia in patients with irritable bowel syndrome who were manifesting diarrhea and in patients with irritable bowel syndrome who were under stress (Preston et al., Gut, 26, 1059-1064 (1985); Fukudo et al., Tohoku J. Exp. Med., 151, 373-385 (1987)) and this suggests the possibility that increased blood motilin levels are involved in the disease. Other diseases that have been reported to involve hypermotilinemia include crohn""s disease, ulcerative colitis, pancreatitis, diabetes mellitus, obesity, malabsorption syndrome, bacterial diarrhea, atrophic gastritis and postgastroenterectomy syndrome. The antagonists of motilin receptors have the potential to ameliorate irritable bowel syndrome and other diseased states accompanied by increased blood motilin levels.
An object of the present invention is to provide ethylamine derivatives that function as an antagonist of motilin receptors and which are useful as medicines.
The present inventors conducted repeated intensive studies in an attempt to develop compounds having an outstanding motilin receptor antagonistic action. As a result, they found that ethylamine derivatives represented by the general formula (1) were an excellent antagonist of motilin receptors. The present invention has been accomplished on the basis of this finding.
Thus, the present invention provides compounds represented by the general formula (1): 
wherein
R1 is an optionally substituted phenyl group, an optionally substituted heterocyclic ring, a straight-chained or branched alkenyl group having 2-6 carbon atoms or a straight-chained or branched alkynyl group having 2-6 carbon atoms;
R2 is a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms, an amino group or a hydroxy group;
R3 is a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms, an optionally substituted amino group or a hydroxy group;
R4 is a hydrogen atom, a methyl group or an ethyl group;
R5 is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-7 carbon atoms or an optionally substituted phenyl group;
R6 is a hydrogen atom, a methyl group or an ethyl group;
R7 is a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms or xe2x80x94COxe2x80x94N(R9)R10;
R8 is an optionally substituted heterocyclic ring having 3-9 carbon atoms or the general formula (2) 
xe2x80x83R9 and R10, which may be the same or different, each represent a hydrogen atom or an optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms;
R11 is a hydroxy group or a halogen atom;
R12, in the case where R11 is a hydroxy group, represents a substituted straight-chained or branched alkyl group having 1-6 carbon atoms, a substituted straight-chained or branched alkenyl group having 2-6 carbon atoms, a substituted straight-chained or branched alkynyl group having 2-6 carbon atoms, a straight-chained or branched acyl group having 2-6 carbon atoms, a straight-chained or branched alkylsulfonyl group having 1-5 carbon atoms or an amino group mono- or di-substituted with straight-chained or branched alkyl groups having 1-5 carbon atoms, and R12, when R11 is a halogen atom, represents an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkynyl group having 2-6 carbon atoms, a straight-chained or branched acyl group having 2-6 carbon atoms, a straight-chained or branched alkylsulfonyl group having 1-5 carbon atoms or an amino group mono- or di-substituted with straight-chained or branched alkyl groups having 1-5 carbon atoms;
X is a carbonyl group or a methylene group; and
Y is a carbonyl group or a methylene group;
or hydrates or pharmaceutically acceptable salts thereof.
The present invention also provides a medicine containing a compound of the general formula (1) as an active ingredient. Further, the present invention provides a motilin receptor antagonist composition containing the compound. The present invention also provides a gastrointestinal motility suppressor agent containing the compound as an active ingredient. Further, the present invention provides a therapeutic of hypermotilinemia containing the compound as an active ingredient.
In the definition of the compounds represented by the general formula (1), exemplary substituents for the optionally substituted phenyl group as R1 include a halogen atom, a hydroxy group, an amino group, a carboxyl group and a methyl group, with a halogen atom and a hydroxy group, particularly a fluorine atom, being preferred.
The optionally substituted phenyl group as R1 is exemplified by a phenyl group optionally substituted with one or more of the above substituents, which may be the same or different; examples include a phenyl group, a para-fluorophenyl group and a para-hydroxyphenyl group, with a phenyl group and a para-fluorophenyl group being particularly preferred.
The heterocyclic ring of the optionally substituted heterocyclic ring as R1 is exemplified by aliphatic or aromatic 5- to 10-membered monocyclic or fused rings containing at least one hetero atom selected from among O, N and S; specific examples include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-oxazolyl and 3-indolyl groups.
Exemplary substituents for the optionally substituted heterocyclic ring as R1 include a halogen atom, a hydroxy group, an amino group, a carboxyl group and a straight-chained or branched alkyl group having 1-3 carbon atoms.
Examples of the optionally substituted heterocyclic ring as R1 are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-oxazolyl and 3-indolyl groups and the like.
Preferred examples of the straight-chained or branched alkenyl group having 2-6 carbon atoms as R1 are straight-chained or branched alkenyl groups having 4-6 carbon atoms.
Preferred examples of the straight-chained or branched alkynyl group having 2-6 carbon atoms as R1 are straight-chained or branched alkynyl groups having 3-6 carbon atoms.
While R1 has the definitions set forth above, R1 is preferably a phenyl group, a para-fluorophenyl group, a para-hydroxyphenyl group, a 2-pyridyl group, a 2-thiazolyl group or a 3-indolyl group.
In its definition of R2, the alkyl group of the optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms is preferably a methyl group.
Exemplary substituents for the optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms as R2 include a halogen atom with a fluorine atom being preferred. The alkyl group may optionally have one or more of these substituents, which may be the same or different.
The optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms as R2 is preferably a methyl group, an ethyl group, a fluoromethyl group or a trifluoromethyl group, with a methyl group being particularly preferred.
While R2 has the definitions set forth above, R2 is preferably a hydrogen atom or a methyl group.
In its definition of R3, the optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms is preferably a methyl group.
Exemplary substituents for the optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms as R3 include a halogen atom with a fluorine atom being preferred. The alkyl group may optionally have one or more of these substituents, which may be the same or different.
The optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms as R3 is preferably a methyl group or a trifluoromethyl group, with a methyl group being particularly preferred.
Exemplary substituents for the optionally substituted amino group as R3 include a straight-chained or branched alkyl group having 1-3 carbon atoms, with a methyl group being preferred. The amino group may optionally have one or more of these substituents, which may be the same or different.
The optionally substituted amino group as R3 is preferably an amino group, a methylamino group, a dimethylamino group or an ethylamino group, and among them, an amino group and a methylamino group are preferred, with an amino group being particularly preferred.
While R3 has the definitions set forth above, R3 is preferably a hydrogen atom or an amino group.
R4 is preferably a hydrogen atom or a methyl group.
In its definition of R5, the alkyl group of the optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms is preferably a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a 3-pentyl group or a neopentyl group.
Exemplary substituents for the optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms as R5 include a phenyl group, a toly group, a para-hydroxyphenyl group, a para-fluorophenyl group, a cycloalkyl group having 3-7 carbon atoms and a halogen atom, with a phenyl group, a cyclohexyl group and a fluorine atom being preferred.
The optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms as R5 is preferably a methyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a 3-pentyl group, a neopentyl group, a 1,1,1,3,3,3-hexafluoro-2-propyl group, a benzyl group, a para-hydroxybenzyl group or a cyclohexylmethyl group.
The cycloalkyl group having 3-7 carbon atoms as R5 is preferably a cyclopentyl group or a cyclohexyl group.
Exemplary substituents for the optionally substituted phenyl group as R5 include a hydroxy group, an amino group, a methyl group, an ethyl group and a halogen atom.
The optionally substituted phenyl group as R5 is preferably a phenyl group.
While R5 has the definitions set forth above, R5 is preferably a methyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a 3-pentyl group, a neopentyl group, a 1,1,1,3,3,3-hexafluoro-2-propyl group, a cyclohexyl group, a phenyl group, a benzyl group, a para-hydroxybenzyl group or a cyclohexylmethyl group.
R6 is preferably a hydrogen atom or a methyl group.
In its definition of R7, the alkyl group of the optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms is preferably a methyl group.
Exemplary substituents for the optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms as R7 include an amino group, a methylamino group, a dimethylamino group, a hydroxy group, methoxy group and a halogen atom, with an amino group being preferred. The alkyl group may optionally have one or more of these substituents, which may be the same or different.
The optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms as R7 is preferably a methyl group or an aminomethyl group, with a methyl group being particularly preferred.
In its definition of R9 and R10 in xe2x80x94COxe2x80x94N(R9)R10 as R7, the optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms is preferably a methyl group or an ethyl group, with a methyl group being more preferred.
While R7 has the definitions set forth above, R7 is preferably a methyl group, a carbamoyl group, a methylcarbamoyl group or a dimethylcarbamoyl group.
The heterocyclic ring of the optionally substituted heterocyclic ring having 3-9 carbon atoms as R8 is exemplified by aliphatic or aromatic 5- to 10-membered monocyclic or fused rings containing at least one hetero atom selected from among O, N and S; specific examples include indole, indoline, indolinone, benzofuran, 2,3-dihydrobenzofuran, furan, thiophene, pyrrole, oxazoline, thiazoline, imidazole, pyridine and pyrimidine, with indole, indoline, indolinone, furan and pyridine being preferred.
Exemplary substituents for-the optionally substituted heterocyclic ring having 3-9 carbon atoms as R8 include: a straight-chained or branched alkyl group having 1-4 carbon atoms which may be substituted with a halogen atom, a hydroxy group, etc., as exemplified by a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a trifluoromethyl group and a hydroxymethyl group; a carboxyl group; a carbamoyl group; a sulfamoyl group; and a hydroxy group. Among them, a methyl group and a tert-butyl group are preferred. The heterocyclic ring may optionally have one or more of these substituents, which may be the same or different.
The optionally substituted heterocyclic ring having 3-9 carbon atoms as R8 is preferably a 3-methylindol-5-yl group, a 3,3-dimethylindolin-5-yl group, a 3,3-dimethylindolinon-5-yl group, a 5-tert-butyl-4-carbamoylfuran-2-yl group, a 5-tert-butyl-4-sulfamoylfuran-2-yl group, a 5-tert-butyl-4-hydroxymethylfuran-2-yl group, a 2-tert-butyl-pyridin-4-yl group or a 5-tert-butyl-4-carboxyfuran-2-yl group.
In its definition of R11 in general formula (2) as R8, a hydroxy group and a fluorine atom are preferable.
When R11 in general formula (2) as R8 is a hydroxy group, the alkyl group of the substituted straight-chained or branched alkyl group having 1-6 carbon atoms as R12 in general formula (2) is preferably a straight-chained or branched alkyl group having 1-4 carbon atoms; specific examples include an isopropyl group and a tert-butyl group.
When R11 in general formula (2) as R8 is a hydroxy group, the alkenyl group of the substituted straight-chained or branched alkenyl group having 2-6 carbon atoms as R12 in general formula (2) is preferably a branched alkenyl group having 3-5 carbon atoms.
When R11 in general formula (2) as R8 is a hydroxy group, the alkynyl group of the substituted straight-chained or branched alkynyl group having 2-6 carbon atoms as R12 in general formula (2) is preferably a straight-chained or branched alkynyl group having 3-5 carbon atoms.
When R11 in general formula (2) as R8 is a hydroxy group, the substituents for the substituted straight-chained or branched alkyl group having 1-6 carbon atoms, the substituted straight-chained or branched alkenyl group having 2-6 carbon atoms and the substituted straight-chained or branched alkynyl group having 2-6 carbon atoms as R12 in general formula (2) are preferably a halogen atom, with a fluorine atom being particularly preferred. The alkyl, alkenyl and alkynyl groups may optionally have one or more of these substituents, which may be the same or different.
When R11 in general formula (2) as R8 is a hydroxy group, the substituted straight-chained or branched alkyl group having 1-6 carbon atoms as R12 in general formula (2) is preferably a perfluoroisopropyl group, a 1,3-difluoro-2-propyl group or a perfluoro-tert-butyl group, with the perfluoroisopropyl group being more preferred.
When R11 in general formula (2) as R8 is a hydroxy group, the substituted straight-chained or branched alkenyl group having 2-6 carbon atoms as R12 in general formula (2) is preferably a branched alkenyl group which has 3-5 carbon atoms and which is substituted with at least one fluorine atom.
When R11 in general formula (2) as R8 is a hydroxy group, the substituted straight-chained or branched alkynyl group having 2-6 carbon atoms as R12 in general formula (2) is a straight-chained or branched alkynyl group which has 3-5 carbon atoms and which is substituted with at least one fluorine atom.
When R11 in general formula (2) as R8 is a hydroxy group or a halogen atom, the straight-chained or branched acyl group having 2-6 carbon atoms as R12 in general formula (2) is preferably an acetyl group, a propionyl group, a butyryl group, an isobutyryl group or a pivaloyl group.
When R11 in general formula (2) as R8 is a hydroxy group or a halogen atom, the straight-chained or branched alkylsulfonyl group having 1-6 carbon atoms as R12 in general formula (2) is preferably a methanesulfonyl group, an ethanesulfonyl group, an isopropylsulfonyl group or a tert-butylsufonyl group.
When R11 in general formula (2) as R8 is a hydroxy group or a halogen atom, the amino group mono- or di-substituted with a straight-chained or branched alkyl group having 1-5 carbon atoms as R12 in general formula (2) is preferably a dimethylamino group, an ethylmethylamino group, a diethylamino group, an isopropylamino group, an ispropylmethylamino group, a tert-butylamino group, a tert-butylmethylamino group, a sec-butylamino group, a sec-butylmethylamino group, an isobutylamino group or an isobutylmethylamino group.
When R11 in general formula (2) as R8 is a halogen atom, the alkyl group of the optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms as R12 in general formula (2) is preferably a straight-chained or branched alkyl group having 1-4 carbon atoms, as specifically exemplified by an isopropyl group and a tert-butyl group.
When R11 in general formula (2) as R8 is a halogen atom, the alkenyl group of the optionally substituted straight-chained or branched alkenyl group having 2-6 carbon atoms as R12 in general formula (2) is preferably a branched alkenyl group having 3-5 carbon atoms.
When R11 in general formula (2) as R8 is a halogen atom, the alkynyl group of the optionally substituted straight-chained or branched alkynyl group having 2-6 carbon atoms as R12 in general formula (2) is preferably a straight-chained or branched alkynyl group having 3-5 carbon atoms.
When R11 in general formula (2) as R8 is a halogen atom, the substituents for the optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, the optionally substituted straight-chained or branched alkenyl group having 2-6 carbon atoms and the optionally substituted straight-chained or branched alkynyl group having 2-6 carbon atoms as R12 in general formula (2) are preferably a halogen atom, with a fluorine atom being particularly preferred. The alkyl, alkenyl and alkynyl groups may optionally have one or more of these substituents, which may be the same or different.
When R11 in general formula (2) as R8 is a halogen atom, the optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms as R12 in general formula (2) is preferably an isopropyl group, a tert-butyl group, a perfluoroisopropyl group, a 1,3-difluoro-2-propyl group or a perfluoro-tert-butyl group, with a tert-butyl group being particularly preferred.
When R11 in general formula (2) as R8 is a halogen atom, the optionally substituted straight-chained or branched alkenyl group having 2-6 carbon atoms as R12 in general formula (2) is preferably a unsubstituted branched alkenyl group having 3-5 carbon atoms.
When R11 in general formula (2) as R8 is a halogen atom, the optionally substituted straight-chained or branched alkynyl group having 2-6 carbon atoms as R12 in general formula (2) is preferably a unsubstituted straight-chained or branched alkynyl group having 3-5 carbon atoms.
While R8 has the definitions set forth above, R8 is preferably a 3-acetyl-4-hydroxyphenyl group, a 4-hydroxy-3-propionylphenyl group, a 3-butyryl-4-hydroxyphenyl group, a 4-hydroxy-3-perfluoroisopropylphenyl group, a 3-dimethylamino-4-hydroxyphenyl group, a 3-tert-butyl-4-fluorophenyl group, a 3-methylindol-5-yl group, a 3,3-dimethylindolin-5-yl group, a 3,3-dimetylinidolinon-5-yl group, a 5-tert-butyl-4-carbamoylfuran-2-yl group, a 5-tert-butyl-4-sulfamoylfuran-2-yl group, a 5-tert-butyl-4-hydroxymethylfuran-2-yl group, a 2-tert-butyl-pyridin-4-yl group, a 5-tert-butyl-4-carboxyfuran-2-yl group, with a 3-butyryl-4-hydroxyphenyl group, a 3-tert-butyl-4-fluorophenyl group, a 3-metylindol-5-yl group and a 5-tert-butyl-4-carboxyfuran-2-yl group being particularly preferred.
X is preferably a carbonyl group or a methylene group.
Y is preferably a carbonyl group or a methylene group.
Preferred examples of the compounds of the general formula (1) 
wherein R1, R2, R3, R4, R5, R6, R7, R8, X and Y have the same meanings as defined above
include Phe-N-Me-Val-Phe(3-acetyl-4-hydroxy)xe2x80x94NH2, Phe-N-Me-Val-Phe(4-hydroxy-3-propionyl)xe2x80x94NH2, Phe-N-Me-Val-Phe(4-hydroxy-3-isobutyryl)xe2x80x94NH2, Phe-N-Me-Val-[3-(5-tert-butyl-4-sulfamoyl-2-furyl)]Ala-NH2, Phe-N-Me-Val-[3-(3-methylindol-5-yl)]Ala-NH2, Phe-N-Me-Val-N-Me-[3-(3-methylindol-5-yl)]Ala-NH2, Phe-N-Me-Val-Phe(3-tBu-4-F)xe2x80x94NH2, Phe-N-Me-Val-N-Me-Phe(3-tBu-4-F)xe2x80x94NH2 and Phe-N-Me-Val-N-Me-Phe(4-hydroxy-3-isobutyryl)xe2x80x94NH2 and more preferred examples are Phe-N-Me-Val-Phe(4-hydroxy-3-isobutyryl)xe2x80x94NH2, Phe-N-Me-Val-[3-(3-methylindol-5-yl)]Ala-NH2, Phe-N-Me-Val-N-Me-[3-(3-methylindol-5-yl)]Ala-NH2, Phe-N-Me-Val-Phe(3-tBu-4-F)xe2x80x94NH2, Phe-N-Me-Val-N-Me-Phe(3-tBu-4-F)xe2x80x94NH2 and Phe-N-Me-Val-N-Me-Phe(4-hydroxy-3-isobutyryl)xe2x80x94NH2.
Salt-forming acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid and trifluoroacetic acid.
The compounds of the present invention can occur as optical isomers and the respective optical isomers and mixtures thereof are all included within the scope of the invention.
The compounds of the present invention can also be obtained as hydrates.
On the pages that follow, the present invention is described more specifically and the amino acids that constitute peptides, the amino acids protected by protecting groups, the protecting groups and reagents are represented by the following abbreviations: Ala: alanine, Val: valine, Phe: phenylalanine, Z: benzyloxycarbonyl, Boc: tert-butoxycarbonyl, BOP: benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate, PyCIU: chloro-N,N,Nxe2x80x2,Nxe2x80x2-bis(tetramethylene)formamidinium hexafluorophosphate, DIC: N,Nxe2x80x2-diisopropylcarbodiimide, HOBT: 1-hydroxylbenzotriazole monohydrate, NMM: N-methylmorpholine, TEA: triethylamine, DIEA: diisopropylethylamine, TFA: trifluoroacetic acid, THF: tetrahydrofuran, DMF: N,N-dimethylformamide and CMPI: 2-chloro-1-methylpyridinium iodide.
The subject application claims priority on the basis of Japanese Patent Application No. 10-307784 and all disclosures in its specification shall be incorporated herein by reference.
The compounds represented by the general formula (1) 
wherein R1, R2, R3, R4, R5, R6, R7, R8, X and Y have the same meanings as defined above can basically be produced by binding Compound (I), Compound (II) and Compound (III), which are represented by the following formulae and in which functional groups other than those involved in bond formation are protected as required: 
The compound of the general formula (1) may be produced by first binding Compound (II) and Compound (III) and then binding the resultant compound with Compound (I). Alternatively, the compound of formula the (1) may be produced by first binding Compound (I) and Compound (II) and then binding the resultant compound with Compound (III).
The compounds of the present invention may be produced by either the solid-phase process or the liquid-phase process. In the production by the solid-phase process, an automatic organic synthesizer can be used but it may be replaced by the manual procedure.
Almost all amino acids that are used for the production of the compounds of the present-invention are commercially available and readily purchasable. Those which are not commercially available can be produced by well-known established methods such as the Strecker synthesis, the Bucherer method, the acetamido malonic ester method, the method of alkylating an amino group protected glycine ester and the Z-xcex1-phosphonoglycine trimethylester method.
Compound (I), if it has a functional-group such as an amino group and a hydroxy group, with the functional group being protected, is a carboxylic acid (X is xe2x80x94CO2H), an aldehyde (X is xe2x80x94CHO), an alkylhalide (X is xe2x80x94CH2xe2x80x94Hal), a sulfonate (X is xe2x80x94CH2xe2x80x94OSO2R) or the like. In this case, bond can be formed by reacting X of Compound (I) with the amino group of Compound (II).
Compound (II) can in almost all cases be derived from an xcex1-amino acid and Y is a carboxyl group (xe2x80x94CO2H), a formyl group (xe2x80x94CHO), a halomethyl group (xe2x80x94CH2xe2x80x94Hal), a sulfonyloxymethyl group (RSO2Oxe2x80x94CH2xe2x80x94) or the like. The amino group of Compound (II) is reacted with X of Compound (I) to form bond and Y of Compound (II) is reacted with the amino group of Compound (III) to form bond.
Compound (III) is an ethylamine derivative and can be derived from an amino acid if R7 is not hydrogen. If R7 is hydrogen, Compound (III) can be synthesized by introducing an amino group to, for example, R8xe2x80x94CH2CHO, which may be obtained from R8xe2x80x94CHO via, for example, a homologation reaction. The amino group of Compound (III) is reacted with Y of Compound (II) to form bond.
When X or Y is a carboxyl group, various methods known in peptide synthesis may be used to activate the carboxyl group for condensation with the amino group and such methods include the use of BOP, the use of PyCIU, the use of bromotripyrrolidino phosphohium hexafluorophosphate (PyBrop), the use of chlorotripyrrolidino phosphonium hexafluorophosphate (PyClop), the use of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), the use of DIC, the use of N-ethyl-Nxe2x80x2-3-dimethylaminopropyl carbodiimide (WSCI), the use of dicyclohexyl carbodiimide (DCC), the use of diphenylphosphorylazide (DPPA), the combination of one of these reagents with HOBT or N-hydroxysuccinimide (HONSu), the mixed acid anhydride method using isobutyl chloroformate or the like, the method of changing the carboxyl group to a pentafluorophenyl ester (OPfp), a p-nitrophenyl ester (ONP) or an N-hydroxysuccinimide ester (OSu), and the combination of one of these methods with HOBT. If necessary, a base such as TEA, DIEA, NMM or 4-dimethylaminopyridine (DMAP) may be added to accelerate the reaction.
A compound in which X or Y is a methylene group can be synthesized from an aldehyde by a conventional reductive bond forming reaction with an amino group or from a halide or sulfonate by substitution reaction with an amino group.